Chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriasis are debilitating diseases affecting millions of people.
RA is a systemic, chronic, inflammatory disease affecting approximately 1-2% of the world's population. The manifestations of RA are usually most severe in the joints. The most frequently affected joints are the proximal interphalangeal and metacarpophalangeal joints in the hands and the metatarsophalangeal joints in the feet. The shoulders, elbows, knees, ankles, and wrists are also common targets of RA. Joints affected by RA ("active" joints) are characteristically tender. Accordingly, RA sufferers often experience pain and impaired mobility. While the severity and progression of RA vary considerably among affected individuals, RA patients as a group have twice the mortality rate of their unaffected counterparts. This decrease in life expectancy appears to be due in part to the side effects of current RA treatments.
In the initial stages of RA, the synovium of the affected joint becomes enlarged and inflamed. Expansion of the synovium is accompanied by angiogenesis and neovascularization. This, in turn, facilitates infiltration into the area by plasma cells, lymphocytes, and macrophages. As inflammatory cells accumulate within it, the synovium becomes edematous and hyperplastic. Neutrophils infiltrate the synovial fluid and cluster on the surface of the synovium. Fibrin deposition also occurs in the joint space. The synovial fluid increases in volume and turbidity with the accumulation of neutrophils, mononuclear cells and occasional red blood cells.
Chronic inflammation causes the synovium to thicken and extend over the particular surface, forming villi which project into the joint space. This aberrant and highly vascularized structure is called a pannus. The pannus invades and erodes the underlying cartilage, with the most active cartilage destruction occurring at the interface between pannus and cartilage. Cartilage destruction is effectuated by collagenase and metallo-proteinases secreted by the inflammatory cells of the pannus. Erosion eventually extends to the subchondral bone, articular capsule and ligaments. Osteoclastic molecules released by the inflammatory cells and synoviocytes allow the synovium to penetrate into the bone and form juxto-articular erosions, subchondral cysts, and osteoporosis.
After the cartilage has been destroyed, the pannus fills the entire joint space, laying down fibrous bands which bridge the opposing bones. As this fibrous ankylosis becomes calcified, a resulting bony ankylosis forms which fuses the opposing bones and prevents the joint from functioning.
RA is an autoimmune disease wherein patients have antinuclear antibodies and antibodies directed at autologous proteins such as immunoglobulin G (IgG), collagen, and cytoskeletal filamentous proteins. Rheumatoid factors (RFs) are autoantibodies found in serum and synovial fluid which bind to the Fc portion of IgG. RFs have been implicated in the pathogenesis of RA. When RFs bind IgGs, complement-activating immune complexes are formed. Activated complement causes the release of vasoactive and chemotactic substances which attract neutrophils and macrophages to the immune complex. As these cells ingest and destroy the immune complexes, they release molecules which cause inflammation and protein degradation and which attract other cells that contribute to RA pathogenesis. Because RFs are synthesized in joints and RFs of the IgG class are self-associating, immune complexes are frequently localized to joints. Nevertheless, immune complexes do circulate in some patients and are thought to cause the extra-articular manifestations of RA such as rheumatoid nodules, reactive amyloidosis and acute vasculitis.
The evidence that RA has autoimmune origins is supported by the finding that injecting avian type II collagen into rats or mice causes them to develop antibodies that recognize the rodent's endogenous collagen. The resulting auto-immune response, which is known as "collagen arthritis," mimics the physiological symptoms of RA such as joint inflammation (Trentham et al., Autoimmunity to type II collagen: an experimental model of arthritis, J. of Experimental Medicine, 146: 857 (1977); Courtenay et al., Nature, 283: 666). Collagen arthritis is a well established model system for the study of RA (Staines & Wooley, Collagen arthritis-what can it teach us?, British Journal of Rheumatology, 1994, 33: 798 (1994)).
The primary method for treating RA is through the administration of drugs which suppress the immune system or reduce inflammation. The two main classes of inflammation inhibitors are corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs).
Corticosteroids are not favored RA medications because, although they can achieve dramatic short-term improvements in RA, long-term treatment is not advisable due to serious side effects and diminished effectiveness of the drug. Short-term corticosteroid treatment is also far from ideal because arthritis symptoms rapidly reappear, often with increased severity, after treatment has stopped. Although corticosteroids such as prednisone can suppress clinical symptoms of RA, the drugs do not prevent RA-mediated joint destruction. Furthermore, typical corticosteroid side effects include: peptic ulcer, hypertension, diabetes mellitus, and glaucoma.
NSAIDs such as aspirin, ibuprofen, and indomethacin are frequently prescribed for RA. Although these drugs can reduce swelling in active joints by inhibiting prostaglandin synthesis, their poor penetration of joint spaces necessitates administration of high doses, and such high doses tend to cause gastrointestinal irritation, ulceration, and bleeding. NSAIDs affect prostaglandin-regulate processes not associated with the inflammation process. NSAIDs are also potent renal toxins, and so are also inadequate for treatment of RA.
Patients with severe active RA may be treated with immunosuppressants such as cyclophosphamide, methotrexate, and azathioprine. While they can reduce inflammation, these drugs affect the patient's entire immune system and have serious side effects including liver disease, bone marrow suppression, and increased risk of malignancy.
Other RA medications include penicillamine, chloroquine, hydroxychloroquine, and gold salts. All have potentially serious side effects. D-penicillamine can cause bone marrow suppression, proteinuria, and nephrosis. Deaths resulting from penicillamine treatment have also been reported. Patients treated with hydroxychloroquine or chloroquine must be monitored for signs of irreversible retinal damage. Gold can induce toxic reactions in the form of dermatitis, renal failure or hepatitis, and its efficacy at treating arthritis is questionable.
Psoriasis sufferers include approximately 1-3% of the population in the United States and an even higher percentage of Northern Europeans. Psoriasis is a chronic inflammatory skin disease in which the patient's skin exhibits recurrent erythematous plaques. These appear as white or silvery, scaling lesions on the skin, especially in the area of the scalp, elbows, knees, back, and buttocks. The accompanying burning and itching may cause discomfort. In severe forms, severe arthritis or exfoliation develops, as well.
The psoriatic lesions exhibit epidermal hyperplasia, infiltration of inflammatory cells, and abnormalities of dermal capillary networks. They are believed to result from epithelial cell hyperproliferation, neovascularization, and, of course, the infiltration of inflammatory cells into the area. Angiogenesis is believed to be necessary to maintain the inflammation and direct neutrophils and lymphocytes into the psoriatic lesion. Additionally, psoriasis patients have autoantibodies directed at the stratum corneum. These autoantibodies are implicated in the pathogenesis of the disease.
Current treatment for psoriasis includes lubricating creams or oils, keratolytics, and topical corticosteroids. For severe forms of the disease, methotrexate may be given, but its high potential for toxicity requires rigidly controlled treatment conditions, including careful monitoring of hematologic, renal, and hepatic finction. Treatment for psoriatic arthritis is similar to that for RA, with some exceptions. For example, antimalarials may aggravate the underlying psoriasis.
RA and psoriasis are diseases characterized by unregulated angiogenesis. Vascular endothelial growth factor (VEGF) has been implicated in driving such unregulated angiogenesis by stimulating endothelial cells lining nearby microvessels to proliferate and begin the process leading to new blood vessel formation. There is evidence that VEGF receptors are overexpressed by endothelial cells that line the blood vessels supplying the inflammatory reactions leading to these disorders. (Dvorak, Int. Arch. Allergy. Immunol., 107;233-235(1995).
What is needed is a treatment method for chronic inflammatory diseases such as RA and psoriasis. There is a need for a compound which inhibits the signs and symptoms of these diseases, and particularly reduces the pain, inflammation, joint swelling, and lesions associated with these diseases. Furthermore, what is needed is a treatment method, and particularly a compound, which is easy to administer and which is nontoxic.